Prostate cancer (PCa) is the most diagnosed cancer among men in developed countries including the United States with significant medical cost burdens. Tremendous advances have been made in PCa screening technologies, which allow early detection and treatment. Common treatment options include radical prostatectomy, external beam radiation therapy (RT) and interstitial RT (brachytherapy), cryotherapy, and androgen deprivation therapy (ADT). Despite these advances, more than a quarter million men still die globally from the disease every year due primarily to treatment-resistance and metastasis. The androgen receptor (AR) expression state is one of the key hallmarks of PCa sustenance and progression. ADT, the first-line treatment option for symptomatic metastatic PCa, starves tumor of growth-promoting androgen hormones such as testosterone. ADT drugs (called antiandrogens) in clinical use, either as monotherapy or combination therapy (with castration), include bicalutamide (Casodex), nilutamide (Nilandron), and flutamide (Eulexin). In the early stage, PCas respond well to ADT and other available therapies. However, malignant cells that survive 2- 3 years will typically enter an antiandrogen-resistant (i.e. castration-resisant or hormone refractory) state and subsequently exhibit chemotherapy-resistance. This castration-resistant state is incurable. Therefore, there is an unmet medical need for increasingly selective and potent drugs to treat castration-resistant stage of PCa. The specific focus of the studies in this proposal is to explore the tumor AR expression state to affect a selective delivery of an independent anti-tumor chemotype, in this case histone deacetylase inhibitor (HDACi). Our choice of HDAC as a therapeutic target is informed by the fact that HDAC inhibition is a clinically validated anti-cancer strategy that is selectively cytotoxic to transfored cells. HDACi have stimulated huge excitement in oncology recently, with close to 500 clinical trials initiated to date, resulting in two clinically approved drugs, SAHA (Zolinza) and FK228 (Istodax), for the treatment of cutaneous T-cell lymphoma. However, current HDACi have serious limitations resulting from poor biodistribution, including ineffectively low concentrations in solid tumors and off-target toxicity, which is hampering clinical progress. The proposed research will solve two problems of main stream cancer therapy agents - resistance development of antiandrogens and lack of tumor accumulation of HDAC inhibitors - to furnish a novel class of targeted agents with potential to positively impact prostate cancer treatment.